title: Molecular basis of autosomal dominant hypercholesterolemia: assessment in a large cohort of hypercholesterolemic children.
abstract: BACKGROUND
  Autosomal dominant hypercholesterolemia (ADH) is characterized by elevated low-density lipoprotein cholesterol levels and premature cardiovascular disease. Mutations in the genes encoding for low-density lipoprotein receptor (LDLR), apolipoprotein B (APOB), and proprotein convertase subtilisin/kexin 9 (PCSK9) underlie ADH. Nevertheless, a proportion of individuals who exhibit the ADH phenotype do not carry mutations in any of these 3 genes. Estimates of the percentage of such cases among the ADH phenotype vary widely. We therefore investigated a large pediatric population with an unequivocal ADH phenotype to assess the molecular basis of hereditary hypercholesterolemia and to define the percentage of individuals with unexplained dyslipidemia.
  
  
  RESULTS
  We enrolled individuals with low-density lipoprotein cholesterol levels above the 95th percentile for age and gender and an autosomal dominant inheritance pattern of hypercholesterolemia from a large referred pediatric cohort of 1430 children. We excluded children with thyroid dysfunction, nephrotic syndrome, autoimmune disease, liver disease, primary biliary cirrhosis, and obesity (body mass index >75th percentile for age and gender), as well as children referred via a cascade screening program and those from families with a known molecular diagnosis. Of the 269 children who remained after the exclusion criteria were applied, 255 (95%) carried a functional mutation (LDLR, 95%; APOB, 5%).
  
  
  CONCLUSIONS
  In the vast majority of children with an ADH phenotype, a causative mutation can be identified, strongly suggesting that most of the large-effect genes underlying ADH are known to date.
authors.affiliation: Academic Medical Center, Department of Pediatrics, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands.
authors.forename: Anouk
authors.initials: A
authors.lastname: van der Graaf
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Avis
authors.forename: D Meeike
authors.initials: DM
authors.lastname: Kusters
authors.forename: Maud N
authors.initials: MN
authors.lastname: Vissers
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Hutten
authors.forename: Joep C
authors.initials: JC
authors.lastname: Defesche
authors.forename: Roeland
authors.initials: R
authors.lastname: Huijgen
authors.forename: Sigrid W
authors.initials: SW
authors.lastname: Fouchier
authors.forename: Frits A
authors.initials: FA
authors.lastname: Wijburg
authors.forename: John J P
authors.initials: JJ
authors.lastname: Kastelein
authors.forename: Albert
authors.initials: A
authors.lastname: Wiegman
mesh_terms: D000293:Adolescent; D001055:Apolipoproteins B / Q000097:blood / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D008078:Cholesterol, LDL / Q000097:blood; D015331:Cohort Studies; D005260:Female; D005838:Genotype; D006801:Humans; D006938:Hyperlipoproteinemia Type II / Q000235:genetics*; D008297:Male; D009154:Mutation; D010641:Phenotype; D011973:Receptors, LDL / Q000235:genetics
chemical_list: D001055:Apolipoproteins B; D008078:Cholesterol, LDL; D011973:Receptors, LDL